Evaluate Renal Function With Semaglutide Once Weekly - American College of Cardiology (2024)

Contribution To Literature:

The FLOW trial showed that among patients with CKD and DM2, once weekly subcutaneous semaglutide was superior to placebo in improving renal and CV outcomes over a median follow-up of 3.4 years.

Description:

The goal of the trial was to compare the safety and efficacy of semaglutide among patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (DM2).

Study Design

Patients were randomized in 1:1 fashion to once weekly subcutaneous semaglutide (n = 1,767) or matching placebo (n = 1,766). An 8-week dose-escalation regimen was used, with dose escalation (as long as unacceptable side effects did not occur) from 0.25 mg per week for 4 weeks and 0.5 mg per week for another 4 weeks, followed by a maintenance dose of 1.0 mg per week throughout the remainder of the treatment period.

• Total screened: 5,581
• Total randomized participants: 3,533
• Median duration of follow-up: 3.4 years
• Median patient age: 66.6 years
• Percentage female: 30.3%

Inclusion criteria:

• DM2 with glycated hemoglobin (HbA_1c) ≤10%
• High-risk CKD (estimated glomerular filtration rate [eGFR] 25-75 mL/min/1.73 m² with a urinary albumin-to-creatinine ratio of >300 and <5000 if the eGFR was ≥50 mL/min/1.73 m² or a urinary albumin-to-creatinine ratio of >100 and <5000 if the eGFR was 25 to <50)
• Receiving a stable maximal labeled dose (or the maximal dose without unacceptable side effects) of renin-angiotensin system inhibitors (angiotensin-converting enzyme inhibitor [ACEi]/angiotensin receptor blocker [ARB])

Other salient features/characteristics:

• White race: 65.8%, Asian: 23.9%
• Median body weight: 89.6 kg
• Median body mass index: 32 kg/m²
• Mean HbA_1c: 7.8%
• Mean blood pressure (BP): 138.6/76.4 mm Hg
• Baseline mean eGFR: 47 mL/min/1.73 m²
• Previous myocardial infarction (MI)/stroke: 22.9%
• Baseline medications: ACEi, 35.1%; ARB, 60.2%; diuretic, 50.4%; lipid-lowering therapy, 80.2%; sodium–glucose cotransporter 2 (SGLT2) inhibitor, 15.6%

Principal Findings:

The trial was terminated early due to efficacy. The primary endpoint, major kidney disease events (a composite of onset of kidney failure; initiation of long-term dialysis, kidney transplantation, or a reduction in the eGFR to <15 mL/min/1.73 m² sustained for ≥28 days), a sustained (for ≥28 days) ≥50% reduction in eGFR from baseline, or death from kidney-related or cardiovascular [CV] cause, for semaglutide vs. placebo, was: 18.7% vs. 23.2% (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.66-0.88, p = 0.0003).

Key secondary outcomes for semaglutide vs. placebo:

• All-cause mortality: 12.8% vs. 15.8%, HR 0.80, 95% CI 0.67-0.95
• CV mortality: 7.0% vs. 9.6%, HR 0.71, 95% CI 0.56-0.89
• Nonfatal MI: 2.9% vs. 3.6%, HR 0.80, 95% CI 0.55-1.15
• Change in HbA_1c from baseline to week 104: -0.87 vs. -0.06 (p < 0.05)
• Change in body weight from baseline to week 104: -5.55 kg vs. -1.45 kg (p < 0.05)
• Mean change in systolic BP: -3.79 vs. -1.55 mm Hg (p < 0.05)
• Mean change in diastolic BP: -0.23 vs. -1.01 mm Hg (p < 0.05)

Interpretation:

The results of this trial show that among patients with CKD and DM2, once weekly subcutaneous semaglutide was superior to placebo in improving renal and CV outcomes over a median follow-up of 3.4 years. Reductions in all-cause and CV mortality were also noted. A modest reduction in body weight (4.1 kg greater weight loss), HbA_1c (0.81% greater reduction), and systolic BP (~2.2 mm Hg greater reduction) was observed between baseline and 104 weeks. Semaglutide slowed eGFR loss by 1.16 mL/min/m². These are landmark findings and are likely to have a major impact on the management of CKD and DM2.

A similar improvement in renal outcomes with SGLT2 inhibitors has been reported before. In this trial, approximately 15% of patients were on these agents at baseline. Although the p-value for interaction was negative and the sample size small (n = 550), patients on SGLT2 inhibitors did not appear to have the same benefit for the primary endpoint numerically. Head-to-head comparisons between these agents as well as potential combination use will need to be explored in future trials.

References:

Perkovic V, Tuttle KR, Rossing P, et al., on behalf of the FLOW Trial Committees and Investigators. Effects of Semaglutide on Chronic Kidney Disease in Patients With Type 2 Diabetes. N Engl J Med 2024;May 24:[Epub ahead of print].